Project Summary/ Abstract: A NOVEL SMALL MOLECULE CX3CR1 ANTAGONIST HALTS METASTASIS Evidence in pre-clinical and clinical settings suggests the involvement of chemokines in metastatic tumor cell disease spreading. We have designed and synthesized the first novel, potent, small molecule CX3CR1 antagonist probe, JMS-17-2. JMS-17-2 is a potent selective CX3CR1 functional antagonist (pERK IC50 = 0.32 nM; Chemotaxis IC50 ? 10 nM). JMS-17-2 is effective in vivo, as it potently blocks tumor cell seeding to the skeleton and slows metastatic progression in a mouse model of established metastasis. The improved advanced lead, JMS-FX-68 (pERK IC50 ? 1 nM) shows impressive survival data in a preliminary 16 week in vivo efficacy study, and importantly appears to demonstrate an effective and safe survival outcome. Specific aims of this proposal are: Specific Aim 1: Specific Aim 1: Identify a compound with improved liver microsome stability while maintaining good drug-like properties. Goal: To clearly provide Drug-like property and selectivity assessment for the top analogs. Specific Aim 2: Complete full characterization of JMS-FX-68 to provide Development Candidate Assessment. Goal: To clearly assess Development candidate criteria for this advanced pre-clinical lead compound. Specific Aim 3: Identification and characterization of a fast follow-up to JMS-FX-68. Goal: To clearly assess Development candidate criteria for an advanced pre-clinical follow-up lead compound. An inhibitor of metastatic dissemination will advance clinical practice and improve therapy by directly addressing tumor spreading, the direct cause of mortality in patients with advanced disease. Synergy of a CX3CR1 antagonist and a chemotherapeutic is expected due to preventing CTCs from entering the sanctuary of the bone marrow. Evidence shows that CX3CR1 antagonism extends to oncology indications such as breast adenocarcinoma, prostate, epithelial ovarian carcinoma, pancreatic cancer, and glioma. Thus, it is envisioned that an efficacious drug to treat metastatic progression would be widely applicable and have a significant impact on the morbidity and mortality associated with metastatic disease.